Leukemia (1997) 11, 1817–1820  1997 Stockton Press All rights reserved 0887-6924/97 $12.00

THP-COPBLM (, , , , and ) regimen combined with granulocyte colony-stimulating factor (G-CSF) for non-Hodgkin’s lymphoma in elderly patients: a prospective study N Niitsu and M Umeda

First Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan

THP-COPBLM including pirarubicin (THP) , which is thought to clinical stage II or higher, and was of intermediate- or high- be less toxic than , was used to treat non- grade malignancy according to the Working Formulation Hodgkin’s lymphoma (NHL) and the remission rate and adverse classification.3 The patients had a performance status (PS) of effects were studied in 26 patients older than 70 years. Com- 4 plete remission (CR) was achieved in 19 patients (73.1%) and 0–3 on the WHO scale. Those having a left ventricular ejec- partial remission in three (11.5%). Classified by stages, CR was tion fraction (LVEF) Ͻ50% and a pulmonary carbon mono- achieved in seven out of nine stage II patients and 12 out of 17 oxidate diffusion capacity (% DLCO) Ͻ60% on pulmonary stage III, IV patients. The 2-year survival rate was 60.3%. Grade functional tests were excluded from the study. The 26 patients 3 or higher adverse effects included leukopenia in eight consisted of 16 men and 10 women with a median age of 77 patients (30.8%), anemia in three (11.5%), thrombocytopenia in years (range 70–88 years). The clinical stage in accordance two (7.7%) and nausea/vomiting in 1 (3.8%). The THP-COPBLM 5 regimen appears useful for the treatment of NHL in elderly with the Ann Arbor classification was II in nine, III in nine, patients. The regimen was seldom associated with gastrointes- and IV in eight. Among the 25 patients having NHL of inter- tinal symptoms and cardiotoxicity. Despite the administration mediate-grade malignancy, the histological type was follicular of granulocyte colony-stimulating factor (G-CSF), however, the large cell (F large) in one, diffuse large cell (D large) in 16, white blood cell count decreased in many patients, suggesting and diffuse mixed cell (D mixed) in eight. One patient had the necessity for further study of this regimen to modify the dose of THP. high-grade NHL of the lymphoblastic type. The PS score was Keywords: non-Hodgkin’s lymphoma; elderly; pirarubicin; granulo- none in 10, one in 8, two in 4, and three in 4. NHL was of cyte colony-stimulating factor the T cell type in eight patients, and of the B cell type in 18.

Administration of Introduction The THP-COPBLM regimen consisted of six 3-week cycles of 2 2 The recent introduction of potent multidrug chemotherapy cyclophosphamide (CPM, 400 mg/m ) and THP (40 mg/m ) regimens for the treatment of non-Hodgkin’s lymphoma (NHL) administrated by intravenous infusion on day 1, vincristine 2 has raised expectations of a high remission rate and a high (VCR, 1 mg/m ; maximum dose, 2 mg) by intravenous injec- 2 long-term survival rate.1,2 Although elderly patients with NHL tion on day 1. Prednisolone (PDN, 40 mg/m ) and procarbaz- 2 are increasing in association with the growing elderly popu- ine (PCZ, 100 mg/m ) orally on days 1–10, and bleomycin lation, such potent chemotherapy regimens are difficult to use (BLM, 10 mg per patient) by intravenous infusion on day 14. on them because of their decreased organ reserve. Accord- Subcutaneous injection of recombinant human granulocyte ␮ ingly, elderly patients have been excluded from many studies colony-stimulating factor (G-CSF, 2 g/kg/day) was adminis- р ␮ on potent chemotherapy regimens, including the third gener- tered when the granulocyte count decreased to 1000/ l, ation regimens, and chemotherapy protocols appropriate for and was discontinued when the white blood cell count у ␮ the elderly have not been investigated sufficiently. increased to 10 000/ l. In patients aged 80 years and over, In the present study, we used the THP-COPBLM the doses of CPM and THP were reduced to 70%. In patients Ͼ (pirarubicin, cyclophosphamide, vincristine, prednisone, having renal dysfunction (creatinine 1.5 mg/dl) or liver dys- Ͼ bleomycin and procarbazine) regimen to treat elderly patients function (total bilirubin 1.5 mg/dl), the doses of THP and with NHL. One of its components is a new , CPM were reduced to 70%. If pulmonary function was abnor- Ͻ pirarubicin (tetrahydropyranyladriamycin, THP), which is less mal (PaO2 60 mmHg or pulmonary carbon monoxide diffus- Ͻ toxic than doxorubicin (DXR). This regimen was evaluated on ing capacity, % DLCO 70%), BLM was withdrawn from the the basis of its remission rate and its adverse effects. regimen, or the dose was reduced to 70% or less. With patients who achieved CR, the dose of THP was 400 mg/m2 at maximum, because only three or four courses of therapy Materials and methods were administered. In order to assess cardiac sympathetic dys- function, 123I-metaiodobenzylguanidine (MIBG) myocardial Materials single photon emission computed tomography (SPECT)6 was performed. An intravenous dose of 3 mCi of 123I-MIBG was The subjects were 26 Japanese patients aged 70 years and injected into the cubital vein, and SPECT images were over with previously untreated NHL. They began to receive obtained using a PRISM-3000 (PICKER) with a versatile col- chemotherapy between April 1994 and June 1996. NHL was limator. The circumferential washout rate (WR) of the left ven- tricle was calculated by the bull’s eye method based on an early image and a delayed image obtained 4 h after injection. Echocardiography was performed at approximately the same Correspondence: N Niitsu, First Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, time as SPECT and the LVEF was calculated. If the WR Tokyo 143, Japan; Fax: 03 3763 8298 exceeded 50%, THP was discontinued, or another anthracyc- Received 21 August 1996; accepted 13 January 1997 line was given as a substitute for THP. THP-COPBLM combined with G-CSF for NHL in elderly patients N Niitsu and M Umeda 1818 Statistical analysis

Therapeutic efficacy was evaluated after at least six cycles (unless the disease was advanced) according to the criteria for evaluation of the efficacy of Solid Cancer Chemotherapy7 were used to assess responses. Survival rates and remission rate curves were calculated according to the Kaplan–Meier method.8 WHO criteria4 were used to define adverse effects.

Results

Therapeutic outcome (Table 1)

Of the 26 patients, 19 (73.1%) achieved complete remission Figure 1 Survival time and disease-free survival of elderly non- (CR) and three (11.5%) achieved partial remission. The overall Hodgkin’s lymphoma patients treated with THP-COPBLM regimen. response rate was 84.6%. Of the 19 patients between 70 and 79 years in age 17 (89.5%) achieved CR. Of the seven patients Adverse effects (Table 2) aged 80 years or over, two (29%) achieved CR. The difference between these two age groups was significant (P Ͻ 0.01). In Adverse effects were rated as grade 0–4 on the WHO criteria. patients having bulky masses у10 cm in diameter, LDH level, Grade 3 or higher hematologic toxicity included leukopenia bone marrow involvement, or a PS of 2–3, the CR rate was in eight patients (30.8%), anemia in three (11.5%), and throm- significantly lower, but there was no significant difference bocytopenia in two (7.7%). Nausea and vomiting occurred in related to the clinical stage, histological type, extranodular one patient, who recovered rapidly after administration of a site, or phenotype (T cell or B cell). 5-HT3 antagonist. Liver and renal dysfunction, hematuria, constipation, diarrhea, and peripheral neuropathy were all transient. Alopecia resolved within 1–6 months after the com- Duration of survival and remission (Figure 1) pletion of treatment. Grade 2 pulmonary dysfunction in one patient was improved after discontinuation of BLM. Use of a The 2-year survival rate was 60.3%. Of the 19 patients who ␤-blocker allowed continuation of THP despite concomitant achieved CR, 51.4% were disease free 2 years after treatment. grade 2 arrhythmia in one patient.

Table 1 Therapeutic effects

CR (%) PR (%) P value

Overall 19/26 (73.1) 3/26 (11.5) Age years 70–79 17/19 (89.5) 1/19 (5.2)  Ͻ у  0.01 80 2/7 (29) 2/7 (28.6) Stage II 7/9 (77.8) 1/9 (11.1)  NS III/IV 12/17 (70.6) 2/17 (11.8) Histology  Intermediate follicular large 1/1 (100) – (–)  diffuse large 12/16 (75) 2/16 (12.5) NS diffuse mixed 6/8 (75) 1/8 (12.5) High  lymphoblastic 0/1 (0) 0/1 (0)  Serum LDH Ͼ normal 10/16 (62.5) 2/16 (12.5)  Ͻ0.05 рnormal 9/10 (90) 1/10 (10)  Bulky mass Ͼ ␾ 10 cm 1/4 (25) 1/4 (25)  Ͻ0.05 р ␾ 10 cm 18/22 (81.8) 2/22 (9.1) Bone marrow involvement 2/5 (40) 0/5 (0) Ͻ0.05 Extranodal site 4/7 (57.1) 1/7 (14.3) NS Performance status 0, 1 15/17 (88.2) 2/17 (11.8)  Ͻ0.05 2, 3 4/9 (44.4) 1/9 (11.1) Phenotype T 5/8 (62.5) 0/8 (0) NS B 14/18 (77.8) 3/18 (16.7) THP-COPBLM combined with G-CSF for NHL in elderly patients N Niitsu and M Umeda 1819 Table 2 Adverse effects increasing as the proportion of elderly individuals in the gen- eral population increases, only a few chemotherapy protocols Grade have been established for them. Thus, it seems to be urgent to devise effective treatment for elderly patients with NHL. 01234 When elderly patients with NHL are treated, the protocol should be individualized. Because immunity is also decreased Leukopenia 3 4 11 5 3 in the elderly, combined use of G-CSF and administration of Anemia 5 5 13 3 0 appropriate antibiotics and antifungal agents will produce a Thrombocytopenia 11 7 6 2 0 Stomatitis 21 5 0 0 0 substantial prognostic improvement. 9 Nausea/Vomiting 18 4 3 1 0 According to Sonneveld et al when patients are relatively Diarrhea 25 1 0 0 0 young or up to 75 years in age and have an excellent PS, Liver dysfunction 23 3 0 0 0 CHOP should be begun at the full dosage. Thus, the dose Renal dysfunction 25 1 0 0 0 should be reduced for more elderly patients. With MACOP- Proteinuria 26 0 0 0 0 B, the risk of death related to chemotherapy is about three Hematuria 24 2 0 0 0 Skin 26 0 0 0 0 times higher in patients aged 60 years and over than in Hair loss 8 12 6 0 0 younger patients. It is believed that advanced age is a contra- Pulmonary dysfunction 24 1 1 0 0 indication for this regimen.2 We have previously used COP- Arrythmia 25 0 1 0 0 BLAM combined with G-CSF to treat elderly NHL patients Constipation 22 4 0 0 0 aged 65 and over, achieving a high remission rate with a low Peripheral neuropathy 24 1 1 0 0 incidence of serious adverse effects (particularly severe infections), and thus reported that this combined therapy was safe.10 COP-BLAM therapy was administered to 36 patients Documented infections aged 65–79 years. It achieved CR in 32 (88.9%) of the 36 patients, with a 4-year survival rate of 60.9%. THP-COPBLM Five (19.2%) of the 26 patients had a temperature у38°C. In therapy achieved CR in 17 (89.5%) out of 19 patients aged three of the five patients, the elevation was associated with a 70–79 years; seven patients aged 80 and over were excluded decrease of the granulocyte count to р1000/␮l. These three from this assessment. Consequently, these two regimens were patients became afebrile when the granulocyte count was nor- not significantly different in efficacy.The WR assessed by malized. Upper respiratory infection occurred in one patient, MIBG exceeded 30% when the doses of ADR and THP 2 2 pneumonia in two, and sepsis in one. Except for the sepsis, exceeded 250–300 mg/m and 350 mg/m , respectively, sug- these infections were improved by treatment with antibiotics gesting the development of cardiac adrenergic dysfunction. G- and antifungal agents. CSF can prevent myelosuppression, permitting the use of high doses of anticancer agents, but other adverse effects may increase as a result of the increased dose intensity. If G-CSF is Cardiotoxicity assessed by 123I-MIBG myocardial combined with anthracycline derivatives which produce free SPECT (Figure 2) radicals,11 elderly patients will become more susceptible to myocardial damage because their ability to detoxify intra- The LVEF assessed by echocardiography showed no changes cellular free radicals is decreased. We previously measured related to chemotherapy in any patient. The total dose of THP the WR, which reflects cardiac sympathetic dysfunction by 123 was directly associated with the WR. In particular, the WR I-MIBG myocardial SPECT in elderly NHL patients who increased when the total dose of THP exceeded 350 mg/m2, received COP-BLAM with G-CSF. This study showed that car- suggesting that THP has the potential to cause cardiac diac sympathetic dysfunction developed when the dose of 2 12 sympathetic dysfunction. DXR exceeded 250–300 mg/m . MIBG is an analog of nore- pinephrine (NE) and is incorporated into sympathetic nerve terminals by a mechanism similar to that for NE. According 13 Discussion to a study in rats by Wakasugi et al, the WR is a useful biochemical marker for dysfunction of the cardiac sympath- The incidence of NHL is higher in the elderly than in younger etic nervous system and such dysfunction associated with the populations. Although elderly patients with NHL have been total dose of DXR and the duration of chemotherapy. THP is a derivative of DXR that has recently been used to treat NHL in elderly patients, because it has less cardiotoxicity and sel- dom produces alopecia and skin disorders. Kitamura14 used the THP-COP regimen (THP, CPM, VCR, PDN) to treat NHL in 144 patients aged 65 years and over, and CR was achieved in 45.1%, with a significantly lower incidence of skin dis- orders such as alopecia when compared with the CHOP regi- men. They reported, however, that the white blood cell count decreased to р2000/␮l in 44.2% of patients receiving THP, which was higher than the rate of 28.5% for the CHOP regi- men. In the present study, to cope with leukopenia due to THP, we used G-CSF. In addition, to detect cardiotoxicity, we not only used electrocardiography and echocardiography, but also 123-MIBG myocardial SPECT. The CR rate of 73.1% and Figure 2 Relationship between washout rate of 123I-MIBG and the 2-year survival rate of 60.3% which we achieved were total dose of pirarubicin. satisfactory if the age of the patients was taken into consider- THP-COPBLM combined with G-CSF for NHL in elderly patients N Niitsu and M Umeda 1820 ation. Although Kitamura et al used THP at doses of 30 mg/m2, 4 World Health Organization. WHO Handbook for Reporting we could increase the dose by 10 mg/m2 to 40 mg/m2 by Results of Cancer Treatment. WHO: Geneva, 1979. administering G-CSF. This increased dose intensity may help 5 Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s disease staging classi- to account for the higher CR rate. The white blood cell count fication. Cancer Res 1971; 31: 1860–1861. was decreased in 30.8% of the patients. Although this rate 6 Niitsu N, Yamazaki J, Igarashi M, Umeda M, Morishita T. Clinical seems to be fairly high, serious infections only occurred in a usefulness of 123I-MIBG myocardial SPECT in patients with adria- few patients, including one death due to septicemia. With mycin-induced cardiomyopathy. Nucl Med 1994; 31: 1051–1057. respect to the cardiotoxicity of THP, the LVEF (as assessed by 7 Draft for the Japanese Cancer Chemotherapy Society Criteria for echocardiography) was not decreased after chemotherapy in Evaluation of the Efficacy of Solid Cancer Chemotherapy. Nippon Gan Chi Shi 1986; 21: 929–941. any patients. 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